FUNDC2 contributes to hypertensive vascular remodeling by regulating mitochondrial dynamics and ferroptosis in perivascular adipose tissue.

OBJECTIVE

Perivascular adipose tissue (PVAT) is closely related to the pathogenesis of vascular remodeling in hypertension. The objective of this study was to explore the specific molecular mechanisms underlying the role of PVAT in the onset and progression of hypertensive vascular remodeling.

METHODS

Thoracic aorta PVAT from male spontaneously hypertensive rats (SHRs) and male Wistar-Kyoto (WKY) rats was used for proteomic analysis, and the differential expression of the identified target proteins was verified by western blotting, immunohistochemistry and transmission electron microscopy (TEM). In vitro, FUN14 domain-containing 2 (FUNDC2) expression was knocked down in 3T3-L1 adipocytes to assess its effects on mitochondrial dynamics, ferroptosis, and adipokine secretion. Next, vascular smooth muscle cells (VSMCs) were cultured in the supernatant of the adipocytes to detect changes in their phenotypic switching and migration.

RESULTS

The proteomic results revealed that the expression of the outer mitochondrial membrane protein FUNDC2 was significantly upregulated in the PVAT of SHRs. Additionally, the expression of key proteins that regulate mitochondrial dynamics and ferroptosis was altered significantly in the PVAT of SHRs compared with the PVAT of WKY rats. Upon FUNDC2 knockdown in 3T3-L1 adipocytes, proteins related to mitochondrial dynamics, ferroptosis, and adipokines reversed the changes in their expression. Moreover, in VSMCs cultured with the supernatant of FUNDC2-knockdown adipocytes, the VSMC phenotype and migration changed.

CONCLUSION

Our findings indicated that increased FUNDC2 expression might lead to PVAT dysfunction and abnormal adipokine secretion, potentially through its link to mitochondrial dynamics and ferroptosis in PVAT adipocytes, therefore leading to hypertensive vascular remodeling.